American Journal of Therapeutics 22, e167–e178 (2015)

Evolving Therapeutic Strategies to Improve Nonsteroidal Anti-inflammatory Drug Safety Bill H. McCarberg, MD1,2 and Byron Cryer, MD3,4,5*

Nonsteroidal anti-inflammatory drugs (NSAIDs) possess potent anti-inflammatory and analgesic properties through inhibition of cyclooxygenase enzymes (COX-1 and COX-2), which are responsible for synthesis of proinflammatory mediators. NSAIDs are frequently used for treatment of acute and chronic pain conditions. However, their use is associated with serious dose-dependent gastrointestinal (GI), cardiovascular, renal, and hepatic adverse effects, which pose a serious clinical concern for both patients and physicians. During the past 2 decades, approaches to improving the tolerability of NSAIDs were mainly directed toward discovery of COX-2 selective NSAIDs (coxibs), which were expected to minimize the risk of GI injury. Unfortunately, the results from multiple clinical studies have shown that treatment with coxibs may increase the risk for cardiovascular complications. This review summarizes current strategies used to reduce the toxicity of NSAIDs and outlines novel therapeutic approaches still in preclinical development. To minimize the risk of GI ulcerations and bleeding, combination therapies with gastroprotective agents are currently recommended. The new therapeutic agents anticipated to have similar effects include nitric oxide– and hydrogen sulfide–releasing NSAIDs. Novel manufacturing technologies enhance dissolution and absorption of NSAID products, allowing for their administration at low doses, which could lead to improved drug tolerability without diminishing the analgesic and antiinflammatory efficacy of NSAIDs. This principle is in line with the current recommendation by the US Food and Drug Administration that NSAIDs should be used at the lowest effective dosage. Finally, NSAID formulations targeted directly to the site of inflammation are expected to reduce systemic drug exposure and thus decrease the risk of systemic adverse effects. Keywords: NSAIDs, pain, COX-2 selective, SoluMatrix, safety

INTRODUCTION Over 30 nonsteroidal anti-inflammatory drugs (NSAIDs) available today1 comprise the most widely used class of drugs in the United States.2 The widespread use of

NSAIDs is a reflection of their well-established antiinflammatory and analgesic efficacy in a variety of acute and chronic pain conditions.3–6 Many guidelines recommended NSAIDs as first-line therapies for various conditions such as acute gouty arthritis,7 osteoarthritis

1

School of Medicine, University of California San Diego, San Diego, CA; 2The Elizabeth Hospice, Escondido, CA; 3Neighborhood Healthcare, Escondido, CA; 4UT Southwestern Medical Center, Dallas, TX; and 5Dallas VA Medical Center, Dallas, TX. Medical writing support was provided by Ewa Wandzioch, PhD and Colville Brown, MD (AlphaBioCom LLC, King of Prussia, PA) and funded by Iroko Pharmaceuticals, LLC. B. H. McCarberg is an advisor for Iroko Pharmaceuticals, LLC, Pfizer, Zogenix, Inc, Collegium Pharmaceutical, Millennium, Mallinckrodt Pharmaceuticals, Inspirion Pharmaceuticals, Salix Pharmaceuticals, Takeda Pharmaceutical Company Limited, Depomed, Inc, Janssen Pharmaceuticals, and Kaleo Pharmaceuticals; he is a stock holder in Johnson and Johnson, Protein Design Labs, Biospecifics Technologies, Nektar Therapeutics, and Galena. B. Cryer has received consulting payments from Iroko Pharmaceuticals, LLC, Ritter Pharmaceuticals, Sanofi Pharmaceuticals, Sandoz Pharmaceuticals, and Cubist Pharmaceuticals. *Address for correspondence: UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390. E-mail: byron.cryer@ UTSouthwestern.edu 1075–2765 Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.

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(OA),8 and migraine headache.9 However, the welldocumented clinical benefit of NSAIDs can be impacted by the risk for serious gastrointestinal (GI), cardiovascular (CV), renal, and hepatic side effects, which are associated with high doses of these agents.10–16 Because of safety concerns, the US Food and Drug Administration issued a recommendation that NSAIDs should be used at “the lowest effective dose for the shortest duration consistent with individual patient treatment goals.”17 During the past 2 decades, numerous approaches to improving the safety and tolerability of NSAIDs have been undertaken. This review aims to outline NSAIDrelated side effects and pharmacologic therapies developed to minimize the risk of adverse events (AEs) associated with NSAID use.

SERIOUS AEs ASSOCIATED WITH THE USE OF NSAIDs Results from multiple clinical studies indicate that NSAIDs may be associated with serious GI, CV, renal, and hepatic AEs.10,13–16 The anti-inflammatory activity of NSAIDs is achieved through the reversible (or in the case of aspirin, irreversible) inhibition of the cyclooxygenase (COX) enzymes COX-1 and COX-2, reducing the synthesis of inflammatory-mediating prostaglandins and thromboxanes.18,19 Reduced synthesis of prostaglandins leads to diminished secretion of the mucus and bicarbonate responsible for protecting gastric mucosa, which increases the risk for GI injury.20,21 The GI adverse effects of NSAIDs include gastroduodenal ulcers, bleeding, and perforation. The majority of these injuries are superficial, but 2%–4% of patients may develop serious complications that lead to gastroduodenal hemorrhage, perforation, or death.10,22 Clinical studies have reported that NSAIDs with high COX-1 selectivity are more likely to be associated with serious GI complications than selective COX-2 inhibitors or traditional NSAIDs with high COX-2 selectivity, such as diclofenac.23,24 In comparison with traditional NSAIDs, COX-2 selective inhibitors were shown to be associated with significantly fewer serious GI AEs.25–28 Prostacyclin (PGI2), a major product of COX-2– mediated metabolism of arachidonic acid in vascular endothelial cells, is a potent vasodilator and platelet inhibitor.29 Current preclinical evidence indicates that selective deletion of COX-2 in the vasculature of mice and subsequent suppression of PGI2 synthesis increases risk for hypertension and thrombosis.30 The COXIB and NSAID Trialist’s Collaboration has published a meta-analysis that assessed risk of CV complications associated with use of both traditional NSAIDs and coxibs.10 Although likely to reduce the risk of GI American Journal of Therapeutics (2015) 22(6)

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toxicity, selective COX-2 inhibitors have been shown to be associated with increased risk for major coronary events.10,31,32 Similar risk has been ascribed to treatment with high doses of traditional NSAIDs such as diclofenac and ibuprofen, but not with high-dose naproxen.10,31 None of the NSAIDs investigated in the above-mentioned meta-analysis were associated with an increased risk of stroke in placebo-controlled trials10; however, a prospective, population-based analysis showed that long-term treatment with any type of NSAID results in an increased risk of stroke.33 The natural role of PGI2 as a vasodilator, natriuretic, and blood pressure homeostatic is important to sustain normal physiological function of the kidney.29,34 Reduced synthesis of PGI2 due to NSAID use may cause renal complications such as peripheral edema, sodium retention, hyperkalemia, and acute renal failure.15 Results of a nested case–control study conducted in patients aged .65 years indicated that the risk of acute renal failure was highest in the first 30 days of NSAID treatment in new NSAID users,15 but cumulative exposure to high doses over a lifetime also significantly increased the risk.35 The use of NSAIDs has been associated with hepatic complications ranging from an increase in aminotransferase levels to serious hepatic injury and acute liver failure.16 Elevations of liver aminotransferase levels are the most common hepatic side effects associated with NSAID treatment. NSAIDs such as sulindac, rofecoxib, and diclofenac have been reported to lead to higher rates of aminotransferase elevations than other NSAIDs.16,36,37 However, serious hepatic AEs leading to clinically apparent liver injury are very rare and estimated to occur in 1–8 cases per 100,000 person-years of NSAID use.37

MATERIALS AND METHODS We performed literature searches in the National Library of Medicine (NLM)/PubMed database to identify relevant publications. The search was limited to articles published from January 01, 1990, to April 30, 2014. Additional specific primary references were obtained by ad hoc searches.

GASTROPROTECTIVE THERAPIES Combination therapies GI events such as gastroduodenal lesions, ulcerations, and bleeding are among the most common AEs associated with NSAID use, and rheumatoid arthritis38 considerable attention has been focused on improving the GI safety of these agents. One therapeutic modality www.americantherapeutics.com

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has been to combine NSAIDs with gastroprotective agents such as synthetic prostaglandin E1 analogs (eg, misoprostol) or therapeutics that suppress gastric acid production such as histamine 2 (H2)-receptor antagonists (eg, famotidine and ranitidine) or proton pump inhibitors (PPIs) (eg, omeprazole and esomeprazole).22 A Cochrane systematic review of randomized controlled trials found that misoprostol, H2-receptor antagonists, and PPIs significantly reduce the risk of developing gastric or duodenal ulcers in patients taking NSAIDs (Table 1).39 However, high doses of H2receptor antagonists were required to reduce the risk of both gastric and duodenal ulcers; at standard doses, the effect of these agents on gastric ulcer prevention was not statistically significant (Table 1).39 Although effective, misoprostol was poorly tolerated, with a high incidence of diarrhea at all doses, which is a wellknown side effect of misoprostol.39,40 In comparative studies, PPIs were better tolerated and more effective than H2-receptor antagonists for preventing all forms of gastroduodenal ulcers, and more effective than misoprostol for preventing duodenal (but not gastric or total) ulcers (Table 1). Fixed-dose combinations Fixed-dose combinations include an NSAID and a gastroprotective agent in a single-dose drug product. Fixed-dose NSAID combinations currently available in the United States include diclofenac sodium–misoprostol (Arthrotec; Pfizer, New York, NY),41 naproxen–esomeprazole magnesium (Vimovo; AstraZeneca, Wilmington, DE), 42 and ibuprofen– famotidine (Duexis; Horizon Pharma, Deerfield, IL).43 Clinical trials with the fixed-dose combination of diclofenac sodium–misoprostol show that it has similar efficacy in relieving the signs and symptoms of

rheumatoid arthritis or OA compared with NSAID monotherapy, but it is associated with a significantly lower rate of gastroduodenal ulcers.44–46 However, patients treated with diclofenac sodium–misoprostol more frequently reported diarrhea.40,45,46 In 2 large randomized, double-blind studies (REDUCE-1 and REDUCE-2), the fixed-dose combination of ibuprofen–famotidine significantly reduced the risk of gastroduodenal ulcers compared with ibuprofen alone.47 As no differences in the incidence of AEs were reported between the ibuprofen–famotidine and ibuprofen monotherapy groups in the REDUCE-1 and -2 studies, the investigators concluded that the high dose of famotidine had no negative impact on tolerability.47 The fixed-dose combination of naproxen–esomeprazole is composed of an enteric-coated naproxen core, surrounded by a layer of immediate-release esomeprazole.42 It is designed to first release the PPI in the stomach and then naproxen in the small intestine.42 In 2 phase 3 randomized, double-blind trials, naproxen–esomeprazole was compared with celecoxib or placebo in patients with OA.48 The combination was significantly more effective than placebo and as effective as celecoxib in reducing pain and improving physical function.48 Naproxen– esomeprazole and celecoxib had generally similar upper GI tolerability profiles, except that patients taking the fixed-dose combination experienced significantly less heartburn than patients taking celecoxib.49 Initiation of gastroprotective therapies in patients treated with NSAIDs has been recommended by multiple health authorities. The American College of Rheumatology’s (ACR) guidelines for the management of OA recommend that when oral NSAIDs are prescribed for patients with knee or hip OA, physicians should consider concomitant prescription of PPIs to limit the risk of upper GI AEs.8 Similarly, the American College of Cardiology Foundation recommends gastroprotective

Table 1. Efficacy of GI ulcer prevention in selected 12-week randomized controlled trials.39 Risk ratio (95% CI) Comparison Misoprostol vs. placebo Misoprostol vs. PPI H2R antagonist vs. placebo High dose Low dose PPI vs. placebo PPI vs. H2R antagonist PPI vs. misoprostol

Gastric ulcer

Duodenal ulcer

Total endoscopic ulcers

0.26 (0.17–0.39) 0.62 (0.33–1.18)

0.42 (0.22–0.81) 3.97 (1.77–8.88)

0.34 (0.20–0.59) 1.11 (0.58–2.13)

0.44 0.73 0.40 0.32 1.61

0.26 0.36 0.19 0.11 0.25

0.41 0.63 0.35 0.28 0.90

(0.26–0.74) (0.50–1.08) (0.32–0.51) (0.17–0.62) (0.85–3.06)

(0.11–0.65) (0.18–0.74) (0.09–0.37) (0.01–0.89) (0.11–0.56)

(0.26–0.63) (0.45–0.88) (0.28–0.43) (0.15–0.51) (0.47–1.72)

H2R, histamine-2 receptor; CI, confidence interval; PPI, proton-pump inhibitor.

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agents in patients who are taking NSAIDs and are at risk of upper GI AEs.50 The guidelines on gastroprotection during NSAID therapy released by the American College of Gastroenterology include recommendations for the choice of NSAID and the need for gastroprotective therapy, based on the patient’s risk of an upper GI event (Table 2), age, history of previous GI ulcers, concurrent use of other medications that increase the risk (aspirin, corticosteroids, and anticoagulants), and NSAID dose.51 These recommendations also take into account the patient’s risk of a CV event, and their need for concomitant antiplatelet therapy (Table 2). Regardless of patients’ risk status, testing for, and treatment of, Helicobacter pylori infections is always recommended.51 Unfortunately, data suggest that US physician adherence to NSAID use guideline recommendations is poor. An analysis of adherence to NSAID prescription guidelines within the Veterans Affairs system showed that 43.0% of veterans who were prescribed NSAIDs in 2002 were considered at high risk for developing upper GI complications. Only 27.2% of these patients were prescribed NSAIDs in adherence with current guidelines.52 Adherence to recommendations for gastroprotectant coadministration in the high-risk group was even lower,

17.8%.52 Similar data were reported in a study of 6507 high-risk NSAID users attending a network of family practices in Wisconsin in which the proportion of highrisk NSAID users who were receiving a gastroprotectant was only 19.6%.53 A managed-care database analysis revealed an even lower rate of gastroprotectant prescription among patients on newly prescribed NSAIDs: 1.4% for patients receiving traditional NSAIDs and 2.6% for patients receiving COX-2 selective agents.54 In light of the finding that patients who are prescribed a PPI along with traditional NSAID therapy face a significantly lower risk of developing upper GI ulcers,54 the low physician adherence to guideline recommendations for gastroprotectant prescription poses a serious concern.

NEW AND EMERGING NSAID FORMULATIONS Topical formulations Topical NSAIDs have been developed to treat local pain and inflammation while reducing circulating levels of the drug and minimizing risk for AEs. Compared with

Table 2. ACG guideline recommendations for NSAID and gastroprotective therapy based on patient risk status.51

Risk of GI toxicity Low (no risk factors*) Moderate (1–2 risk factors) High (.2 risk factors, or history of previously complicated ulcer or concomitant use of corticosteroids or anticoagulants) Other patient groups Patients requiring low-dose aspirin cardioprotection Moderate GI risk and high CV risk† High GI risk and high CV risk†

Recommendation

Level

Strength

Can receive nonselective NSAID at the lowest effective dose COX-2 inhibitor alone or traditional nonselective NSAID + misoprostol or PPI Alternative therapy or if anti-inflammatory treatment absolutely necessary, COX-2 inhibitor + misoprostol or high-dose PPI

1‡

A§

1

B

1

B

Naproxen + misoprostol or PPI

2

C

Naproxen + misoprostol or PPI Avoid NSAIDs or coxibs; prescribe alternative therapy

2 2

C C

*Common risk factors: patient’s age .65 years, comorbidities, high-dose NSAID therapy, concurrent medications, history of ulcers, and H. pylori infection. All patients with a history of ulcers who require NSAIDs should be tested for H. pylori, and if the infection is present, eradication therapy should be prescribed. †High CV risk is arbitrarily defined as the requirement for low-dose aspirin for prevention of serious CV events. ‡Level of evidence: (1) level of evidence strongly in favor of recommendation, (2) level of evidence favors recommendation, (3) level of evidence in favor of recommendation is equivocal, and (4) level of evidence does not favor recommendation. §Strength of recommendations: (1) strong evidence from multiple published, well-controlled randomized trials or a well-designed meta-analysis, (2) strong evidence from at least 1 quality, published randomized controlled trial or evidence from published, welldesigned, cohort or matched case–control studies, and (3) consensus of authoritative expert opinions based on clinical evidence or from well designed, but uncontrolled or nonrandomized clinical trials. COX-2, cyclooxygenase-2 inhibitor; CV, cardiovascular; GI, gastrointestinal; PPI, proton-pump inhibitor.

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Improving Safety of NSAIDs

oral NSAIDs, topical NSAIDs demonstrate lower systemic absorption, and therefore exhibit the potential for a lower incidence of GI, CV, and renal AEs.55 The ACR recommends topical NSAIDs as one of initial therapies suitable for patients with hand or knee OA.8 Although commonly used in the European Union,56 only 3 topical NSAIDs are approved in the United States, all of which are diclofenac sodium formulations: a 1% gel (Voltaren Gel; Novartis Consumer Health Inc, Parsippany, NJ)57; 1.5% topical solution (Pennsaid; Mallinckrodt Brand Pharmaceuticals Inc, Hazelwood, MO)58; and a diclofenac epolamine patch (Flector; King Pharmaceuticals Inc, Bristol, TN; Table 3).62 A large number of randomized controlled clinical trials have evaluated the efficacy and safety of topical diclofenac gel and solution and reported that these products are significantly more effective than placebo in relieving pain and muscle stiffness, and improving physical function in patients with acute and chronic conditions such as ankle sprains60 and OA.61,63–68 Topical diclofenac gel and solution products exhibit comparable efficacy to oral diclofenac67–69 with a lower incidence of GI AEs67,68 (Table 3). Overall, topical NSAID formulations may have improved GI safety profiles compared with oral formulations, but they are most suitable for treatment of a subset of rheumatic conditions that are amenable to targeted therapy. Topical NSAIDs are also associated with application site reactions, which in elderly patients contribute to a discontinuation rate comparable with oral NSAIDs.98 Diclofenac potassium powder for oral solution Sachets containing diclofenac potassium powder admixed with buffering agents enabling prompt systemic absorption of the drug were developed for treatment of acute pain conditions that requires fast onset of analgesia. In clinical studies, diclofenac potassium powder demonstrated fast absorption71 and rapid pain relief in patients with migraine headaches.72,73 After administration of a single 50-mg dose of diclofenac powder dissolved in water, treatment-related AEs were reported to occur in less than 1% of all patients (N 5 343), and included nausea, dyspepsia, vomiting, and dizziness.73 Diclofenac potassium powder for oral solution is currently the only NSAID approved by the FDA for the acute treatment of migraine attacks with or without aura in adults70 (Table 3). ProSorb technology In 2009, the FDA approved a novel liquid–gel capsule formulation of diclofenac potassium (Zipsor; Depomed Inc, Newark, CA) developed using ProSorb technology, which is indicated for the treatment of www.americantherapeutics.com

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mild-to-moderate acute pain at a dose of 25 mg every 6 hours (Table 3).74 In this formulation, diclofenac is combined with dispersing agents that distribute the drug rapidly in the gastric juices, enhancing absorption and resulting in a shorter time to maximum plasma concentration compared with the standard diclofenac potassium tablet.75 In clinical studies, diclofenac potassium liquid-filled soft gelatin 25-mg capsules administered every 6 hours were shown to provide significantly better and faster analgesia compared with placebo in patients with acute pain after third molar extraction (Table 3)76,77 or after bunionectomy.78,79 Diclofenac potassium liquid–gel capsules were generally well tolerated, with the most common AEs being nausea, headache, vomiting, and constipation.79 Because none of these studies have compared the efficacy and tolerability of diclofenac potassium liquid–gel capsules with other available formulations of diclofenac potassium, it is not yet possible to determine whether ProSorb technology has any clinically meaningful impact on the incidence of potentially serious AEs with diclofenac. SoluMatrix fine particle technology Several NSAIDs (diclofenac, indomethacin, meloxicam, and naproxen) are being developed using SoluMatrix fine particle technology (Iroko Pharmaceuticals, LLC, Philadelphia, PA). This technology can produce drug particles that are 200–800 nm in size—up to 20 times smaller than the starting material—without particle agglomeration.80,81 The submicron size and increased particle surface area relative to mass facilitate faster dissolution.80,81 These properties allow for enhanced absorption of the active NSAID ingredient and thereby may facilitate effective treatment at lower doses. Two of the SoluMatrix NSAIDs, low-dose SoluMatrix diclofenac (ZORVOLEX; Iroko Pharmaceuticals, LLC; 18- and 35-mg doses) and low-dose SoluMatrix indomethacin (TIVORBEX; Iroko Pharmaceuticals, LLC; 20- and 40-mg doses) have been approved by the FDA for treatment of mild-to-moderate acute pain in adults. SoluMatrix diclofenac has also recently been approved for management of osteoarthritis pain (Table 3). In phase 1 clinical studies in healthy volunteers, lower doses of both SoluMatrix NSAIDs demonstrated similar absorption, but reduced overall systemic exposure compared with 50-mg doses of either diclofenac potassium immediate-release tablets or indomethacin immediate-release capsules under fasting conditions.86,87 In a randomized phase 3 study, low-dose SoluMatrix diclofenac 35 and 18 mg administered 3 times daily provided significantly greater pain relief over 48 hours and faster onset of analgesia, compared with placebo, in patients with acute pain after bunionectomy.90 Additionally, data from two phase 3 studies: (1) a 12-week American Journal of Therapeutics (2015) 22(6)

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Table 3. New approaches to improving NSAID safety. NSAID formulation (commercial name)

Indication

Topical formulations

Diclofenac sodium topical gel 3% (Solaraze) Diclofenac sodium topical gel 1% (Voltaren)

Primary feature Reduction of circulating levels of NSAID. Local treatment of pain and inflammation60–69

Topical treatment of actinic keratosis59

Relief of the pain of OA of joints amenable to topical treatment, such as the knees, feet, and hands57 Diclofenac epolamine topical patch Topical treatment of acute pain due 1.3% (Flector) to minor strains, sprains, and contusions62 Diclofenac sodium topical solution Treatment of signs and symptoms of 1.5% (Pennsaid) OA of the knee58 Diclofenac potassium powder for oral Acute treatment of migraine attacks Improved absorption enabling fast solution, 50-mg sachets (Cambia) with or without aura in adults70 pain relief71–73 ProSorb technology Diclofenac potassium liquid-filled Relief of mild-to-moderate acute Maximized absorption of diclofenac capsules, 25 mg (Zipsor) pain74 from the stomach to potentially improve its analgesic efficacy and safety76–79 SoluMatrix technology Diclofenac capsules, 18 and 35 mg Treatment of mild-to-moderate acute Improved drug particle dissolution (Zorvolex) pain in adults80 and absorption that can potentially Management of osteoarthritis pain82 allow for efficacy at reduced doses of the drug83–90 Indomethacin capsules, 20 and 40 Treatment of mild-to-moderate acute mg (Tivorbex) pain in adults83 Meloxicam test capsules Investigational product that has been evaluated in patients with OA Naproxen conjugated with nitric oxide Investigational product that has been Nitric oxide–releasing moiety is (Naproxcinod) evaluated in patients with Duchenne expected to provide muscular dystrophy88 gastroprotection91 Compound CG100649 Investigational product Through dual inhibition of COX enzymes and carbonic anhydrase-1/ 2, this compound is anticipated to have improved CV safety profile92 Aspirin, diclofenac and naproxen Investigational products Hydrogen sulfide–releasing moiety is conjugated with hydrogen sulfide expected to provide gastroprotection93 Flurbiprofen conjugated with lipid Investigational products SLNs or nanostructured lipids carriers carriers expected to improve topical and ocular delivery94–96 OEG-conjugated prodrugs of Investigational products Targets NSAIDs directly to the site of indomethacin, sulindac, and inflammation, including the central diclofenac nervous system97 COX, cyclooxygenase; CV, cardiovascular; NSAID, nonsteroidal antiflammatory drug; OA, osteoarthritis.

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Improving Safety of NSAIDs

study and (2) a 12-month study in patients with OA have recently been submitted for publication.89 Comparable efficacy results were obtained from a randomized phase 3 study in patients with postsurgical pain that evaluated the efficacy of 3 doses of SoluMatrix indomethacin: 40 mg 3 times daily, 40 mg twice daily, and 20 mg 3 times daily compared with placebo. All 3 doses of SoluMatrix indomethacin significantly reduced pain intensity over 48 hours and led to reduction in opioid rescue medication usage compared with placebo.83 Both SoluMatrix products were well tolerated and did not cause any treatment-related serious AEs typically associated with NSAID use, such as ulcers, bleeding, or perforation, or any CV, renal, or hepatic complications.83,90 The most frequent non–procedure-related AEs in both phase 3 studies were of mild-to-moderate intensity and included nausea, dizziness, and headache.83,90 Although an active comparator, celecoxib 400 mg loading dose followed by 200 mg twice daily was included in both phase 3 studies, a comparison between the efficacy or safety of SoluMatrix NSAIDs and celecoxib could not be made due to insufficient power of these studies. Further clinical studies are needed to evaluate whether SoluMatrix technology can reduce risk for NSAID-associated side effects. Additionally, the efficacy and safety of 5 and 10 mg doses of investigational SoluMatrix meloxicam are currently being evaluated in clinical studies in patients with OA (ClinicalTrials.gov Identifiers: NCT01801735, NCT01787188). Nitric oxide–releasing NSAIDs Nitric oxide (NO) is a vasodilator that also protects the integrity of the GI mucosa by stimulating excretion of mucus and bicarbonate and inhibiting the release of inflammatory mediators. Within the stomach, the biochemical effects of NO resemble those of prostaglandin E2, the key prostaglandin produced by the action of gastric COX-1.99 It was therefore suggested that adding an NO-releasing moiety to an NSAID molecule could result in an agent that retained the COX-inhibiting effects of NSAIDs with acquired gastroprotective properties through NO action. Such agents would theoretically have less potential to cause mucosal injury compared with traditional NSAIDs. These novel therapeutics are called COX-inhibiting NO donors (CINODs) or NONSAIDs. NO-naproxen (naproxcinod), currently the most advanced among these agents, was developed by the French pharmaceutical company NicOx (Sophia Antipolis, France; Table 3). The efficacy and safety of naproxcinod was evaluated in 3 phase 3 studies and 1 long-term safety extension study in patients with OA of the knee and hip.100–103 The results demonstrated that naproxcinod was www.americantherapeutics.com

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significantly more effective than placebo and comparable in its efficacy to naproxen101–103 and rofecoxib.100 However, no apparent safety benefits were observed when naproxcinod was compared with naproxen or rofecoxib except that naproxcinod did not increase blood pressure compared with placebo, whereas the comparator NSAIDs led to blood pressure elevation.100,102–104 Despite this result, the FDA rejected the naproxcinod application in 2010, due to lack of long-term safety data.105 In 2014, NicOx announced that it had refocused development of naproxcinod for the treatment of muscular dystrophy and has been granted Orphan Drug Designation by the European Commission for this indication.106 Recent results from a long-term preclinical study showed that naproxcinod improved skeletal and cardiac muscle function and reduced skeletal muscle inflammation in an animal model of Duchenne muscular dystrophy.88 Hydrogen sulfide–releasing drugs Similar to NO, hydrogen sulfide (H2S) is a potent vasodilator. Hydrogen sulfide is expressed in the gastric mucosa, where it contributes to gastric protection.90 Because of its gastroprotective role, there has been considerable interest in developing NSAIDs that release H2S, much like the NO-releasing NSAIDs. Derivatives of aspirin, diclofenac, and naproxen able to release H2S are under preclinical development (Table 3).107 In addition, a naproxen hybrid is being developed that contains a hydroxybenzothioamide group, which can release H2S in biological fluids through hydrolysis.107 This strategy may bypass any direct inhibitory effects of H2S on leukocyte adherence. Currently, none of these agents have undergone any clinical trials, but it will be interesting to see whether the H2S-releasing strategy results in an improved GI safety profile in patients, a benefit that was not borne out for the NO-releasing NSAIDs when they were tested clinically. Compound CG100649 The compound CG100649 (CrystalGenomics, Inc, Seoul, South Korea and CG Pharmaceuticals, Inc, Emeryville, CA) represents a novel coxib that is postulated to exhibit dual inhibition of COX enzymes and carbonic anhydrase-1/2 (CA-1/2) (Table 3). The results from preclinical studies in rats revealed that CG100649 partitioned to red blood cells and bound to CA-1/2. It was therefore suggested that this property may translate into reduced NSAID-induced hypertension and diminished CV hazard. However, in a recent active- and placebo-controlled, doubleblind, randomized clinical study in healthy volunteers, CG100649 did not inhibit CA-1/2 activity, although it did partition to erythrocytes.92 Compared with American Journal of Therapeutics (2015) 22(6)

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celecoxib, a tendency toward lower blood pressure was observed, but the study was not sufficiently powered for a conclusive comparison. Thus, it needs to be determined by further clinical studies whether CG100649 can attenuate CV risk compared with other coxibs.92

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facilitate PLA2-targeted release of the OEG-prodrug conjugates in the brain and minimize NSAID-associated adverse effects. The same principle may apply to NSAID prodrugs targeted to specific sites of inflammation, with the additional advantage of high PLA2 expression reported in the inflamed tissues.109

Nanotechnology in topical and ocular delivery Colloidal systems for drug delivery such as solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are 2 main types of lipid nanoparticles developed to facilitate long-term drug release through transdermal or ocular delivery.94,95 They combine the advantages of emulsions, liposomes, and polymeric nanoparticles to prevent chemical degradation of the drug as it passes through the skin. Compared with other topical delivery systems, SLN and NLC are expected to cause less side effects owing to their lipid matrix being composed of biodegradable, nontoxic, physiologically well-tolerated lipids and lipid stabilizers.94 It has been suggested that bioavailability, biocompatibility, and tolerability of NSAIDs can be improved by enclosing drug particles in nanoparticulate lipid carrier systems. Flurbiprofen, a potent NSAID, has been chosen for nanoparticle delivery mostly because of its lipophilic character and short elimination half-life dictating frequent dosing.94 Hence, SLN and NLC flurbiprofen formulations that could facilitate long-term percutaneous or ocular drug delivery would be advantageous. These formulations have already been developed,94,95 but have not yet undergone clinical evaluation (Table 3). Preclinical data suggest that they exhibit good transdermal and ocular penetration, slow drug release, and a low potential for toxicity.94–96 Oligoethylene glycol-substituted terminal amino acid chain of NSAIDs A well-established method for improving a drug’s pharmacokinetic and tolerability profile is to administer it as a prodrug, which is then broken down to the active moiety after being absorbed. Modification of the molecule by conjugation to polyethylene-glycol is already established as a means of prolonging half-life. More recently, oligoethylene glycol (OEG) derivatives have been developed to serve the same function, with the additional benefit of targeting the active drug to the specific sites. Three OEGconjugated prodrug forms of indomethacin, sulindac, and diclofenac have been synthesized (Table 3).97 These compounds contain OEG with chain-terminal biomolecules susceptible to hydrolysis by phospholipase A2 (PLA2). After the cleavage by PLA2, the NSAID prodrugs are released at the site targeted by OEG. As NSAIDs may reduce the prevalence and severity of Alzheimer disease,108 availability of OEG-conjugated NSAIDs could American Journal of Therapeutics (2015) 22(6)

CONCLUSIONS Attempts to improve the safety profile of NSAIDs continue to be an active area of research. While in the 1990s and early 2000s approaches to improving NSAID safety focused on developing new drugs with greater COX-2 selectivity, research efforts since 2010 are notable for strategies aimed at improving the safety of existing agents by administering them along with gastroprotectants, improving their pharmacokinetic properties allowing effective treatment at low doses, or targeting drug delivery directly to the sites of inflammation. It is anticipated that these strategies will limit the risks of AEs associated with these agents, which continue to provide significant pain relief for a substantial patient population with acute and chronic pain. Some of these agents are at an early stage of development, and the lessons from NSAID development over the past 2 decades are important reminders that long-term, largescale comparative clinical studies are needed to confirm that new NSAID formulations can provide clinically meaningful safety benefits.

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